Hydroxy acetal compounds and their preparation



Patented Mar. 10, 1953 UNITED STATS NT 7 OFFICE HYDROXY ACETAL COMPOUNDS AND THEIR PREPARATION David I. Weisblat, Galesburg, and Barney J. Magerlein, Kalamazoo, Mich, assignors to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Application May 8, 1952, Serial No. 286,821

CODE

2 sents zero or the integer l, i. e. those containing either no glutamic acid or ester residue or only one glutamic acid or ester residue, and the method will be described with particular reference thereto,

Compounds having the generic formula given above are of particular value as intermediates in the preparation of compounds similar to or identical with certain naturally occurring compounds of the folic acid group. Thus, as described in the parent application referred to and N- (3,3-diallroxy-2-hydroxypropyl) -N- arylsulfonyl) -p aminobenzoate compounds wherein R is a member of the group consisting of hydrogen and the alkyl radicals and n is a member of the group consisting of zero and the positive integers 1 to '7, inclusive. They thus include N-substitution products of p-aminobenzoic acid, of p-aminobenzoyl-glutamic acid, of paminobenzoyl-glutamyl-glutamic acids having up to seven glutamic acid residues in the molecule, and of their esters, the N-substituent being in each case a 3,3-dialkoxy-2-hydroxypr0pyl radical.

In the structural formulae given herein and in the appended claims aromatic nuclei are repre sented by one or more simple hexagons. In the naming of compounds having the generic formula given and of other compounds mentioned herein wherein both a glutamic acid residue and a paminobenzoic acid residue are included in the molecule, the nitrogen atom of the glutamic acid residue is, for convenience, herein referred to by the symbol N and the nitrogen atom of the jp-aminobenzoic acid residue is referred to by the symbol N. As indicated by the generic formula, compounds used in or prepared by the process of the invention which contain more than one glutamic acid or ester residue are those wherein only the gamma-carboxyl groups are involved in the peptide linkages. Preferred compounds used in or prepared by the method of the invention are those wherein n of the generic formula given, and in those given subsequently reprein concurrently filed co-pending application Serial No. 286,822, the hydroxy acetal esters or acids (III) of the present invention can be oxidized readily to form the corresponding keto acetal esters or acids, respectively, and the latter can be condensed readily with 2,4,5 triamino- S-hydroxypyrimidine to form alkyl N-((2-amino- 4-hydroxy-6-pteridyl) -methyl) p aminobenzoates or dialkyl N-(N-((2-amino-4-hydroxy-6- pteridyl) -methyl) N- (arylsulfonyl) -p aminobenzoyl) -glutamates, or the free acids, depending upon the particular hydroxy acetal started with. These latter compounds can, in turn, by hydrolysis of the ester group with alkalies in the case of the esters, and upon removal of the arylsulfonyl radical, e. g. with hydrogen bromide and a bromine acceptor in an aliphatic acid medium, be converted directly to pteroic acid or to a pteroyl-glutamic acid which latter compound appears to be identical with the L. casei factor or vitamin B0 obtained from liver. The order of the hydrolysis step and the splitting of the arylsulfonyl radical can be reversed, if desired.

Compounds having the generic formulae given in which the glutamic acid residues have the 1(|) configuration are of particular interest because of the existence of glutamic acid residues having the same configuration in folic acid com pounds isolated from natural sources. The method of the invention and the intermediate compounds to be described are, however, not

N-(arylsulfonyl)-p-aminobeuzoate ester (followed by hydrolysis when free acid is desired) (tert. amino catalyst) aryl- 02 III in the process of the invention and in the preparation of the corresponding arylsulfonyl intermediates and final products, the preferred starting materials and intermediate products are those containing the p-toluene-sulfonyl radical due to the ready availability of the p-toluenesulfonyl halides and to the generally crystalline nature of the p-toluenesulfonyl derivatives 01 compounds with which the present invention is concerned. The invention is, however, not limited to compounds containing the p-toluenesul fonyl radical and compounds containing other arylsulfonyl radicals, such as the benzenesulfonyl, o-toluenesulfonyl, naphthalenesulfonyl, methylnaphthalenesulfonyl radicals and others, can be used, if desired.

It should also be mentioned that compounds N -(3,3-dialkoxy-Z-hydroxypropyl)-N (arylsulionyl)-p-aminobenzoate compound The process of the invention, as illustrated in containing arylsulfonyl radicals having non-hythe accompanying reaction chart wherein the formulae of the compounds given are numbered to correspond with the'following description and wherein n and B have the values given previously, comprises the step of reacting a 2,3- oxidopropanal dialkyl acetal (I) with an N- (arylsulfonyl)-p-aminobenzoate ester (II) to give compounds of the invention (III) which are alkyl esters, i. e. wherein R of the generic formula (III) is an alkyl radical. The corresponding acids, 1. e. compounds wherein R, of the generic formula (III) is hydrogen, can be prepared by careful hydrolysis of the esters with alkalies and subsequent acidification of the alkaline mixture.

Certain of the N-(arylsulfonyl)-p-aminobenzoate esters (II) are described and claimed in co-pending application Serial No. 41,888, filed July 31, 1948. They can be prepared readily, as described in the co-pending application just mentioned, by reacting an arylsulfonyl halide with an alkyl ester of p-aminobenzoic acid, of paminobenzoyl-glutamic acid, or of a p-aminobenzoyl-glutamyl-glutamic acid having up to seven glutamic acid residues in the molecule.

Dialkyl acetals of 1,2-oxidopropanal which can be used in the process include the dimethyl, diethyl, di-npropyl, di-iso-propyl, dibutyl, diamyl and other dialkyl acetals. As a matter of convenience and availability dialkyl acetals wherein the alkyl radicals each contain less than 8 carbon atoms are preferred, although others can be used, if desired. It is apparent that the nature of the alkyl groups in the hydroxy acetal radical of the compounds of the invention are determined by the particular 1,2-oxidopropanal dialkyl acet-al (I) used in carrying out the reaction and that the alkyl esters which are formed are determined by the particular N-(arylsulfonyD-p-aminobenzoate esters (II) used.

Esters which can be used as starting compounds in the process, with the production of the corresponding esters (III) of the invention, include the methyl, ethyl, n-propyl, iso-propyl, butyl, amyl, hexyl, nonyl and other alkyl esters. As a matter of convenience, lower alkyl esters containing less than about 8 carbon atoms in the alkyl ester radicals are preferably used in the process, although insofar as is known any alkyl ester can be used.

Although starting compounds containing substantially any arylsulfonyl radical can. be u e drocarbon substituents can be used in the process and the corresponding intermediates and final products prepared, provided only that the substituent is non-reactive under the reaction conditions. Such non-reactive substituents include chlorine, bromine, and the methoxy, phenoxy, nitro and similar radicals. It should be mentioned further that, although the present invention is concerned primarily with compounds wherein the sulfonyl radical is an arylsulfonyi radical, the process can also be carried out and the corresponding products prepared using starting materials containing alkylsulfonyl, aralkylsulfonyl, or cycloalkylsulfonyl radicals, such as the methanesulfonyl, ethanesulionyl, cyclohexylsulfonyl, and phenylmethanesulfonyl radicals.

The reaction of a dialkyl acetal of 2,3-oxidopropanal with an N-(arylsulfonyl)-p-aminoben zoate ester can be carried out readily by heating the substances together, preferably with the addition of a catalytic proportion of pyridine or other tertiary amine. Approximately equimolecular proportions of the reactants can be used and the mixture preferably heated at from about degrees to degrees centigrade for from about 5 to about 60 minutes. The N-(3,3-dialkoxy 2 hydroxypropyl) N (arylsulfonyl) p-arninobenzoate compound formed can be isolated from the reaction mixture, e. g. by washing the crude reaction product thoroughly with a suitable solvent, such as naphtha or isopropanol, to remove the catalyst and unreacted starting materials. Some of the N- (3,3-dialkoxy- 2-hydroxypropyl) -N-(arylsulfonyl) -p-aminobenzoate esters are thus obtained as crystalline compounds having well defined melting points and some as sirupy liquids. They can be hydrolyzed to the corresponding acids by mixing with aqueous alkalies or other conventional hydrolytic agents and acidifying the aqueous reaction mixture, preferably with a mineral acid. Certain of the acids are thus obtained as solid substances.

New compounds represented by the generic formula (III) which can be prepared by the method herein described include, among many others: ethyl N-(3,3-dimethoxy-2-hydroxypropyl) -N- (benzenesulfonyl) -p-aminobenzoate, nhexyl N-( 3,3-di-n-propoxy-2-hydroxypropyl) -N- (o-toluenesulfonyl)-p-aminobenzoate, n-butyl N (3,3-di-n-butoXy'-2-hydroxypropyl) N-(pchrobenzenesulfonyl)--p-aminohenzoate,v diethyl N" (N (3,3 a dimethoxy 2 hydroxypropyll- N (benzenesulionyl) p aminobenzoyl) glutamate, di-n-hexyl N-(N-(3,3-di-n-pr0poXy-2- hydroxypropyl) N (0 toulenesulfonyl) paminebenzoyl) glutamate, di n butyl N- (N (3,3 di iso butoxy 2 hydroxypropyl) N (p bromobenzenesu-lionyl) p aminobenzoyl) glutamate, N (3,3 dimethoxy 2 hydroxypropyl) N (benzenesulfonyl) -p aminobenzoic acid, N-(3,3-di-n-propoxy-2-hydroxypro pyl) N (o toluenesulfonyl) p aminobenzoic acid, N (3,3 di n butoxy 2 hydroxypropyl) N (p chlorobenzenesulfonyl) paminobenzoic acid, N-(N-(3,3-dimethoxy-2-hydroxypropyl) N (benzenesulfonyl) p aminobenzoyl) glutamic acid, N (N (3,3 din propoxy 2 hydroxypropyl) N (o toluenesulfonyl) p aminobenzcyl) glutamic acid, and N-(N-(3,3-di-iso-butoxy-2hydroxy propyl) N (p bromobenzenesulfcnyl) paminobenzoyl) -glutamic acid.

Certain advantages of the invention are apparent from the following examples which are given by way of illustration only and are not to be construed as limiting.

Example 1.Ethyl N-(3,3-diethoary-2-hydroxypropyl) N (p tdtuenesulfonyl) p mmnobenzoate A mixture of one gram of the diethyl acetal of 2,3-oxidopropanal, 1.5 grams of ethyl N-(ptoluenesulfonyl) p-aminobenzoa-te and two drops of pyridine was heated for twelve minutes at 130 to 135 C. The clear melt which was formed was cooled and seeded with crystals of previousiy prepared ethyl N-(3,3-diethoxy-2-hydroxypropyl) N (p toluenesulfonyl) p aminohenzoate. The partially crystalline mass was trit rated with a mixture of six milliliters f petroleum naphtha and three milliliters of isopropanol and the mixture filtered. There was thus oletained 1.71 grams of ethyl N-(3,3-diethoXy-2- hydroxypropyl) N (p toluenesulfonyl) paminobenzoate melting at 89 to 94 C. Repeated recrystallization of the product from isopropanolpetroleum naphtha raised the melting point to 91 to 94 C.

Following substantially the same procedure, but using an equi-molar proportion of the dimethyl acetal of 2,3-oxidopropanal, the di-n-propyl acetal of 2,3-oxidopropanal, the di-n-butyl acetal of 2,3-oxidopropanal, the di-iso-butyl acetal of 2,3-oxidopropanal or of the di-dodecyl acetal of 2,3-oxidopropanal in place of the diethyl acetal of 2,3-oxidopropanal, there are formed ethyl N (3,3 dimethoxy 2 hydroxypropyl) N (p toluenesulfonyl) p aminobenzoatc, ethyl N (3,3 di n propoxy 2 hydroxypropyl) N (p toluenesulfonyl) p aminobenzoate, ethyl N-(3,3-di-n-butoxy-2-hydroxypropyl) N (p toluenesulfonyl) p aminobenzoate, ethyl N-(3,3-diiso-butoxy-2-hy roxypropyl) N (p toluenesulfonyl) p aminobenzoate, and ethyl N-(3,3-di-dodecyloXy-2-hydroxypropyl) l (p toluenesulfonyl) paminohenzoate, respectively.

Following substantially the same procedure, but using equi-molar proportions of ethyl N- (benzenesulfonyl)-p-aminobenzoate, n-he zyl N- toluenesulfonyl) p aminohenzoate, n butyl N (p chlorobenzenesulfonyl) p aminobenzoate, or of n dodecyl N (beta naphthalenesulfonyl) p aminobenzoate in place of the ethyl N (p toluenesulfonyl) p aminobenzoate,'there are obtained'ethyl N=(3,3-diethoxy-2 hydroxypropyl) N (benzenesulfonyl) p aminobenzoate. n hexyl N (3,3-diethoxy-2- hydroxypropyl) N (o toluenesulfonyl) p aminobenzoate, n butyl N (3,3 diethoxy- 2 hydroxypropyl) N (p chlorobenzenesuh fonyl) p aminohenzoate, and n dodecyl N (3,3 diethoxy 2 hydroxypropyl) N (beta napthalenesulfonyl) p aminobenzoate, respectively.

Example 2.-D2'ethyl-N (N (p-toluenesulfonyl) p-aminobeneoyl) -1-glutamate Thirty and nine-tenths grams of N- (p-toluenesulfonyl) -paminobenzoyl chloride and 23.9 grams of diethyl 1(+)-glutamate hydrochloride were dissolved in 300 milliliters of ethylene dichloride and the solution cooled to between 0 and 10 C. The cold solution was stirred vigorously and 22.3 grams of triethylamine in 72 milliliters of ethylene dichloride was added slowly over a period of about 20 minutes. The temperature of the mixture was held between 10 and 20 C. during the addition of. the triethylamine and the mixture then allowed to stand at room temperature for one hour. The mixture was then washed successively with water, dilute hydrochloric acid, saturated aqueous sodium bicarbonate and finally with water. The colorless solution thus obtained was dried with anhydrous sodium sulfate and naphtha was added until the solution became opalescent. The mixture was then cooled to cause crystallization and filtered. The crystals, after drying, consisted of 36 grams of diethyl N (N (p toluenesulfonyl) p aminobenzoyl) 1 glutamate melting at 124 to 126 C.

Example 3.--Dicthyl N (N 3,3 diethozcy 2- hydroxypropyl) N (p toluenesuljonyl) pamz'nobcnzoyl) -1 -glutamate One and six-tenths grams of the diethyl acetal of 2,3-0xidopropanal and five drops of pyridine were added to 4.77 grams of fused diethyl N'- (N (p toluenesulfonyl) p aminobenzoyl) l-glutamate at C. The mixture was stirred for about 30 minutes at to C. The highly colored mass consisted chiefly of diethyl N'- (N (3,3 diethoxy 2 hydroxypropyl) N- (p toluenesulfonyl) p aminobenzoyl) 1- glutamate. It had an index of refraction without further purification of N =l.527.

Following substantially the same procedure, but using an equi-molar proportion of the dimethyl acetal of 2,3-oxidopropanal, the di-npropyl acetal of 2,3-oxidopropanal, the di-nbutyl of 2,3-oxidopropan-al, the di-iso-hutyl acetal of 2,3-oxidopropanal or the di-dodecyl acetal of 2,3-oxidopropanal in place of the diethyl acetal of 2,3-oxidopropanal, there are obtained diethyl N (N (3,3 dimethoxy 2 hydroxypropyl) N (p toluenesulfonyl) p aminobenzoyl) 1 glutamate, diethyl N (N 3,3,- di n propoxy 2 hydroxypropyl) N (ptoluenesulfonyl) p aminoloenzoyl) 1 glutamate, diethyl N (N (3,3 di n butoxy- 2 hydroxypropyl) N (p toluenesulfonylp aminobenzoyl) l glutamate, diethyl N'- (N (3,3 di iso butoxy 2 hydroxypropyl) N (p toluenesulfonyl) p aminobenzoyl) lglutamate, and diethyl N (N (3,3 didodecyloxy 2 hydroxypropyl). N (p toluenesulfonyl) p aminobenaoyl) 1 glutamate, respectively.

a Following substantially the same procedure,

but using an equi molar proportion of diethyl N"- (N (benzenesulfonyl) p aminobenzoyl) 1- lutamate, di n hexyl N" (N (o toluenesulfonyl) p aminobenzoyl) 1 glutamate, din butyl N (N (p chlorobenzenesulfonyD- p aminobenzoyl) l glutamate, or of di ndodecyl N (N (beta-naphthalenesulfonyl)- p aminobenzoyl) 1 glutamate in place of diethyl N (N (p toluenesulfonyl) p aminobenzoyl) 1 glutamate, there are obtained diethyl N (N (3,3 diethoxy 2 hydroxypropyl) N (benzenesulfonyl) p aminobenzoyl) 1 glutamate, di n hexyl N- (N (3,3 diethoxy 2 hydroxypropyl) N- (o toluenesulfonyl) p aminobenzoyl) lglutamate, di n butyl N (N (3,3 diethoxy 2 hydroxypropyl) N (p chlorotoluenesulfonyl) p aminobenzoyl) l glutamate and di n dodecyl N (N (3,3- diethoxy 2 hydroxypropyl) N (beta naphthalenesulfonyl) p aminobenzoyl) 1 glu tamate, respectively.

Example 4.N- (3,3-diethzry-2-hydroxypropyl) N p-toluenesulfionyl) -p-amz'nobenzoic acid A quantity of ethyl N (3,3 diethoxy 2- hydroxyprcpyl) N (p toluenesulfonyl) paminobenzoate is warmed for several minutes N (3,3 di iso butoxy 2 hydroxypropyl) N (p toluenesulfonyl) p aminobenzoic acid, N (3,3 di dodecyloxy 2 hydroxypropyD- N (p toluenesulfonyl) p aminobenzoic acid, N (3,3 diethoxy 2 hydroxypropyD- N (0 toluenesulfonyl) p aminobenzoic acid, N (3,3 diethoxy 2 hydroxypropyl) N- beta naphthalenesulfonyl) p aminobenzoic acid, N (N (3,3 diethoxy 2 hydroxypropyl) N (p toluenesulfonyl) paminobenzoyl) l glutamic acid, N (N (3,3- diethoxy 2 hydroxypropyl) N (p chlorobenzenesulfonyl) p aminobenzoyl) l glutamic acid, N (N (3,3 diethoxy 2 hydroxypropyl) N (benzenesulfonyl) p aminobenzoyl) 1 glutamic acid, and N (N (3,3 diethoxy 2 hydroxypropyl) N (betanaphthalenesulfonyl) p aminobenzoyl) lglutamic acid, respectively.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is, therefore, to be limited only by the scope of the appended claims.

We claim:

1. A compound having the formula COOP.

with slightly more than one molar portion of dilute aqueous or alcoholic sodium hydroxide and the mixture then cooled, diluted, acidified and filtered. There is thus obtained N-(3,3-diethoxy-' 2-hydroxypropyl) N (p toluenesulfonyl) paminobenzoic acid.

Following substantially the same procedure ethyl N (3,3 dimethoxy 2 hydroxypropyl) N (p toluenesulfonyl) p aminobenzoate, ethyl N (3,3 di n propoxy 2 hydroxypropyl) N (p toluenesulfonyl) p aminobenzoate, ethyl N (3,3 di n butoxy 2- hydroxypropyl) N (p toluenesulfonyl) paminobenzoate, ethyl N (3,3 di iso butoxy- 2 hydroxypropyl) N (p toluenesulfonyD- p aminobenzoate, butyl N (3,3 di-dodecyloxy- 2 hydroxypropyl) N (p toluenesulfonyD- p aminobenzoate, n hexyl N (3,3 diethoxy- 2 hydroxypropyl) N (o toluenesulfonyl) p aminobenzoate, n dodecyl N (3,3-diethoxy 2 hydroxypropyl) N (beta naphthalenesulfonyl) p aminobenzoate, diethyl N (N (3,3 diethoxy 2 hydroxypropyl) N- (p to1uenesulfonyl) p aminobenzoyl) lglutamate, di n butyl N (N (3,3 diethoxy 2 hydi'oxypropyl) N (p chloro benzenesulfonyl) p aminobenzoyl) 1 gluaryl- O 2 wherein R is a member of the group consisting of hydrogen and the alkyl radicals and n is a member of the group consisting of zero and the positive integer 1.

2. A compound as claimed in claim 1 wherein the alkyl radicals each contains less than 8 carbon atoms.

3. A compound as claimed in claim 1 wherein R is an alkyl radical and n is the positive integer 1.

l. A compound as claimed in claim 1 wherein the arylsulfonyl radical is the p-toluenesulfonyl radical.

5. Ethyl N (3,3-diethoxy-Z-hydroxypropyl) -N- (p-to-luenesulfonyl) -p-amino-benzoate.

6. Diethyl N'-(N-(3,3-diethoxy-2-hydroxypropyl) N (p toluenesulfonyl) p aminoben zoyl) -g1utamate.

7. The method which includes: reacting a dialkyl acetal of 1,2-oxidopropan-al with an ester having the formula COO-alkyl wherein n is a member of the group consisting of zero and the positive integer 1 to form an hydroxy tamate, diethyl N (N (3,3 diethoxy 2 hy-' ester having the formula droxypropyl) N (benzenesulfonyl) p aminobenzoyl) l glutamate and di dodecyl N- (N (3,3 diethoxy 2 hydroxypropyl) N- (beta naphthalenesulfonyl) p aminobenzoyl) l glutamate are hydrolyzed to form N- (3,3 dimethoxy 2 hydroxypropyl) N ptoluenesulfonyl) paminobenzoic acid, N- (3,3 di n propoxy 2 hydroxypropyl) N- (p toluenesulfonyl) p aminobenzoic acid, N- (3,3 di n butoxy 2 hydroxypropyl) N- (p toluenesulfonyl) p aminobenzoic acid,

aryl-S O 2 alkyl acetal of 1,2-oxidopropanal with an ester having the formula 0 o 0alkyl 11-1 C0(NHCHCHaCHiCO)=O-alkyl aryl-SO:

wherein n is a member 01 the group consisting of zero and the positive integer 1 to form an hydroxy ester having the formula COO-silky] it (alkyl-O-MOB-CH OHCH1-N aryl-SO:

and hydrolyzing the hydroxy esterrwith an alkali to form an hydroxy acid having the formula C O OH (aikyl-O-hClk-CHOH-CHTr-N aryi-- 0: I

'12. The method which includes: heating a mixture comprising the diethyl acetal of 2,3-oxidopropyi) N -(p toluenesulfonyl) p aminoben zoyl) -glutamate.

DAVID I. WEISBLAT. BARNEY J. MAGERLEIN.

No references cited. 

1. A COMPOUND HAVING THE FORMULA
 11. THE METHOD WHICH INCLUDES: REACTING A DIALKYL ACETAL OF 1,2-OXIDOPROPANAL WITH AN ESTER HAVING THE FORMULA 